In U.S. Pat. No. 3,320,124, issued in 1967, there is described and claimed a method for treating coccidiosis with quinazolinone derivatives.
Halogufinone, otherwise known as 7-bromo-6-chloro-3-[3- (3-hydroxy-2-piperidinyl)-2-oxopropyl]-4(3H)-quinazolinone, was first described and claimed in said patent by American Cyanamid Company, and was the preferred compound taught by said patent and the one commercialized from among the derivatives described and claimed therein.
Subsequently, U.S. Reissue Patent No. 26,833 and U.S. Pat. Nos. 4,824,847; 4,855,299; 4,861,758 and 5,215,993 all relate to the coccidiocidal properties of halofuginone, while U.S. Pat. No. 4,340,596 teaches that it can also be used for combatting theileriosis.
In U.S. Pat. No. 5,449,678, there is described and claimed an anti-fibrotic composition, comprising an amount of a compound of formula I: ##STR1## wherein:
n is 1 or 2;
R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy;
R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and
R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl;
and physiologically acceptable salts thereof, effective to inhibit collagen type I synthesis, as active ingredient therein.
After further research and development, it was discovered that the above-identified compounds of formula I are effective in the inhibition of restenosis, which formally is not a fibrotic condition.
The pathogenesis of atherosclerosis involves abnormal migration and proliferation of smooth muscle cells (SMCs) infiltrated with macrophages and embedded in extracellular matrix (ECM) of adhesive glycoproteins, proteoglycans and collagens [V. Fuster, et al., "The Pathogenesis of Coronary Artery Disease and the Acute Coronary Syndromes," New Eng. J. Med., Vol. 326, pp. 242-250 (1992); R. Ross, "The Pathogenesis of Atherosclerosis: A Perspective for the 1990's," Nature, Vol. 362, pp. 801-809 (1993)]. Under physiological conditions, the majority of arterial SMCs remains in the Go phase and cell growth is controlled by a balance between endogenous proliferation-stimulating and proliferation-inhibiting factors. Following endothelial cell perturbation due to atherogenic risk factors (i.e., hypertension, hyperlipoproteinemia, diabetes mellitus), platelets and non-platelet-derived growth factors and cytokines are released and stimulate monocyte and SMC migration as well as SMC proliferation (V. Fuster, et al., ibid.; R. Ross, ibid.). Among these growth factors are platelet-derived growth factor (PDGF) [G. A. A. Ferns, et al., "Inhibition of Neoinitmal Smooth Muscle Accumulation after Angioplasty by an Antibody to PDGF," Science, Vol. 253, pp. 1129-1132 (1991)], basic fibroblast growth factor (bFGF) [V. Lindner, et al., "Role of Basic Fibroblast Growth Factor in Vascular Lesion Formation," Circ. Res., Vol. 68, pp. 106-113 (1991)], and interleukin-1 (IL-1) [H. Loppnow and P. Libby, "Proliferating or Interleukin-1 Activated Human Vascular Smooth Muscle Cells Secrete Copious Interleukin 6," J. Clin. Invest., Vol. 85, pp. 731-738 (1990)]. Macrophages and platelets also release enzymes, i.e., elastase, collagenase, heparanase) that digest various constituents of the ECM and release bFGF and possibly other growth factors (TGFb) that are stored in basement membranes and ECM [I. Vlodavsky, et al., "Extracellylar Matrix-bound Growth Factors, Enzymes and Plasma Proteins," in: Molecular and Cellular Aspects of Basement Membranes, Monographs in Cell Biology, D. H. Rohrbach and R. Timpl, Eds., Academic Press, New York, N.Y., U.S.A., pp. 327-346 (1993)]. A potent growth-promoting activity towards SMCs is also exerted by thrombin, which, under certain conditions, may be present within the vessel wall [R. Bar-Shavit, et al., "Thrombin Immobilized to Extracellular Matrix Is a Mitogen for Vascular Smooth Muscle Cells: Non-Enzymatic Mode of Action," Cell Reg., Vol. 1, pp. 453-463 (1990); S. M. Schwartz, "Serum-Derived Growth Factor is Thrombin?" J. Clin. Invest., Vol 91, p. 4 (1993)]. Molecules that interfere with the growth-promoting activity of these growth factors may attenuate the progression of the atherogenic process.
Proliferation of arterial smooth muscle cells (SMC) in response to endothelial injury is a basic event in the process of restenosis of coronary arteries after percutaneous transluminal coronary angioplasty (PTCA) [V. Fuster, et al., ibid.]. Coronary bypass surgery or angioplasty are applied to reopen coronary arteries that have been narrowed by heart disease. A major problem with both procedures in that arteries rapidly reclog in about 30% of patients undergoing antioplasty and about 10% bypass surgery patients. Vascular SMC are ordinarily protected by the smooth inner lining of the arteries, composed of vascular endothelial cells. However, following bypass surgery or angioplasty, SMC are often left exposed. In a futile effort to repair the wound, the cells proliferate and clog the artery.
According to the invention claimed in Israel Specification No. 110,831, there is provided a pharmaceutical composition comprising a compound of formula I as hereinbefore defined, in a pharmaceutically effective amount for preventing restenosis by the inhibition of vascular smooth cell proliferation and in combination with a pharmaceutically acceptable carrier.
In preferred compositions of said invention, said compound is halofuginone.
As is known, conventional balloon angioplasty, introduced over 15 years ago, remains hampered by the persistence of two vexing problems: abrupt vessel closure during intervention and restenosis during follow-up. Mechanical intervention with intracoronary stents was introduced for human clinical investigation already in 1986, and following FDA approval of the first coronary stent for prevention of restenosis following balloon angioplasty, the market for the devices has grown from $220 million in 1994 to one that is expected to capture as much as $1 billion in world-wide revenues in 1996 [W. Diller, "Technology Strategies--Coronary Stents: Breaking J&J's Lock on the Market," Start-Up, pp. 20-26 (May 1996)].
According to said article, while angioplasty alone may result in restenosis rates of 40% or more, some studies indicate that angioplasty, followed by stent deployment, reduces the rate to 20-30%, depending on the kind and location of disease.
Obviously, a restenosis rate of 20-30% is also undesirable, and therefore it has been suggested in the literature, and there are now manufactured and sold, stents which are coated with materials designed to reduce restenosis. Thus, e.g., Johnson & Johnson International Systems markets a heparin-coated form of the Palmaz-Schartz stent and Medtronic Interventional Vascular markets a fibrin-coated Wiktor stent. Stents coated with an antithrombogenic silicon-carbide material have been sold by Biotronik GmbH, and other suggestions include the coating of metallic stents with polymers to diminish their thrombogenic properties, with a nylon mesh, and with a medical grade silicon polymer. Drug-eluting polymer coatings have also been reported [see, e.g., Tao Peng, et al., "Role of Polymers in Improving the Results of Stenting in Coronary Arteries," Biomaterials 1996, Vol. 17, No. 7, pp. 685-694 (1996)]. Thus, said article teaches that polymer stents can incorporate or bind drugs for later local controlled delivery at the target site that would inhibit thrombus formation and neointimal proliferation and that local administration of various drugs, including urokinase, heparin, taxol, hirudin and peptide, is being investigated to prevent thrombosis and restenosis.